The lack of proper medicaments to prevent and/or stop the spread of HIV among sexual partners has been well documented. See J. Cohen, Science, (Oct. 15, 2004) 306; J. Turpin, Expert. Opin. Investig. Drugs, (August 2002) 11(8), 1077-1097; R. Trager, Science, (Jan. 3, 2003), 299. Infection with HIV leads to Acquired Immunodeficiency Syndrome (“AIDS”) or AIDS Related Complex (“ARC”) in over 90% of untreated infected individuals within a ten-year period. As the HIV epidemic continues to threaten millions of people worldwide, new strategies to prevent the spread of the virus are desperately needed. In the absence of an effective preventative vaccine, alternative methods of preventing HIV infection are currently being explored.
HIV typically establishes an infection by first attaching to CD4 receptors on white blood cells and then grabbing a second receptor known as CC Chemokine Receptor 5 (“CCR5”), which normally responds to immune chemicals called chemokines. Epidemiological and viral transmission studies have shown that viruses using the CCR5 receptor are often associated with transmission of HIV infection between individuals. Therefore blocking these viruses by prophylactic treatment with a specific CCR5 inhibitor should prove an effective way to prevent HIV transmission in a susceptible population. For example, M. Lederman et al, Science (Oct. 15, 2004) 306, 485-487 describe a study of the ability of N.sup.alpha.-(n-nonanoyl)-des-Ser.sup.1-[L-thioproline.sup.2, L-.alpha.-cyclohexyl-glycine.sup.3] RANTES (“PSC-RANTES”) to prevent acquisition of SHIV infection at a mucosal skin. Q. Hu et al, J. Exp. Med. (Apr. 19, 2004) 199(8), 1065-1075 describe the blockade of the effect of both CCR5 and CXCR4 to prevent infection.
However, successful prevention of HIV infection may be best achieved with using a combination of anti-virals which each prevent infection through a different mechanism. Thus combining a CCR5 inhibitor with antiviral compounds which act as inhibitors of HIV replication can be effective methods of preventing HIV infections. Such inhibitors of HIV replication include reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. Integrase has also shown to play a role in viral replication. The inhibition of integrase in vitro and of HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells.
One solution to the need to administer CCR5 receptor antagonists in combination with an inhibitor of HIV integrase or other inhibitors of HIV replication in an intra-vaginal ring (IVR). However, simultaneous drug release of two or more therapeutic agents from an IVR is challenging because two or more drugs have to be released from one device and multiple sets of pre-defined drug release criteria must be fulfilled in order for the system to be effective. Several different IVR designs have attempted to provide specific controlled release solutions, mostly for contraceptives, but few have been successful.
Most, if not all of the current IVRs, including those described in the following patents and applications: U.S. Pat. Nos. 3,995,633; 3,995,634; 4,237,885; European patent publication 0,050,867; U.S. Pat. Nos. 4,292,965; 4,596,576; PCT publication WO 97/02015; European Patent 876 815; PCT publication WO2009/036999 and PCT publication WO2004/103336, suffer from at least one of the following drawbacks: lack of stability upon storage and transport, inability to independently adjust the release rate of multiple therapeutic components, difficulty or expense in manufacturing, inability to meet necessary release criteria to achieve the desired therapeutic effect and complexity of design.
Examples of known IVRs are described in scientific literature, e.g. Malcolm et al, Vaginal rings for delivery of HIV microbicides, International Journal of Women's Health, 2012:4 595-605, gives an overview of the current state-of-the-art in microbicide delivery via IVRs. Several complex solutions for releasing multiple compounds are described such as the “pod-ring” and the multi segmented polyurethane ring. In addition, reference is made to the disadvantages of the so-called reservoir rings compared to matrix type rings. Most notably their complex manufacture and low release rates.
The systems disclosed in EP 876 815 and the PCT publications WO2009/036999 and WO2004/103336 set the standard when manufacturability of IVRs suitable for simultaneous drug release at large-scale is concerned. Specifically, WO2004/103336 discloses a reservoir type drug delivery system comprising at least one compartment consisting of (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with (a) crystals of a first pharmaceutically active compound and with (b) a second pharmaceutically active compound in dissolved form and wherein said core is loaded with said second compound in dissolved form.
Although the system disclosed in WO2004/103336 is suitable for the independent release of many drug combinations, the latter can still be improved upon particularly with regard to the capacity of releasing a wide range of drugs, including anti-virals, at sufficiently high rates to achieve the desired therapeutic effect.
Drug release from the WO2004/103336 system in certain cases is too much restrained by the low drug permeability of the rate limiting skin surrounding the reservoir. Additionally, examples exemplified in WO2004/103336 include a diffusion path through the membrane which is identical for all drugs loaded in the reservoir. As a consequence varying membrane properties will affect all drugs essentially equally and hence the release is tuned in the same direction—all up or all down—and the ratio in which the dissolved and crystalline drug are released remains essentially unaffected.
Additionally, the IVRs exemplified in WO2004/103336 suffer from the further limitation that the release of the dissolved drug is tuned to its desired rate by dissolving the right amount in the reservoir. It appears that this specific amount, resulting in the exact right concentration needed to obtain the desired release, is directly proportional with the saturation solubility (CA,s) and inversely proportional with the release rate of the crystalline drug (dMa/dt). Low saturation solubility means a small driving force for diffusion and hence higher release rates for the crystalline drug can only be achieved if thin skins are applied. The release of drug depends on the amount dissolved and on the thickness of the skin. If the same target release rate for drug is to be matched with a thinner skin, less of drug should be dissolved in the core. So, the flipside of applying too thin skins is that the amount of dissolved drug becomes too small resulting in early depletion and steeply declining release profiles hampering broad application of the concept disclosed in WO200/103336.
This phenomenon can also be explained mathematically. The steady state drug release rate for cylindrical reservoir systems can be described mathematically by the following equation:
                                          d            ⁢                                                  ⁢            M                                d            ⁢                                                  ⁢            t                          =                              2            ⁢            π            ⁢                                                  ⁢            L            ⁢                                                  ⁢            D            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                                ln            ⁡                          (                                                r                  0                                                  r                  i                                            )                                                          (        1        )            in which:                dM/dt is the release rate [kg/s]        L is the length of the cylinder [m]        r0 is outer radius of the skin [m]        ri is the inner radius of the skin [m]        D is the drug in polymer diffusion coefficient m2/s        ΔC is the concentration gradient over the skin [kg/m3]        DΔC Is drug permeability kg/m·sFor thin layers equation (1) can be approximated by:        
                                          d            ⁢                                                  ⁢            M                                d            ⁢                                                  ⁢            t                          =                              2            ⁢            π            ⁢                                                  ⁢            L            ⁢                                                  ⁢            D            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                    d                                    (        2        )            in which d is the skin thickness [m]From equation (2) it follows that the skin thickness is proportional with the drug permeability (DΔC) and inversely proportional with drug release (dM/dt) rate:
                    d        ∝                              D            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                                              d              ⁢                                                          ⁢              M                                      d              ⁢                                                          ⁢              t                                                          (        3        )            Under sink conditions the concentration at the skin surface (r=r0) is zero and equation (3) reduces to:
                              d          ∝                                    D              ·              C                                                      d                ⁢                                                                  ⁢                M                                            d                ⁢                                                                  ⁢                t                                                    ,                            (        4        )            where C is the concentration in the skin at the interface (r=ri)
In WO2004/103336 the crystalline drug in the intermediate layer and the dissolved drug loaded in core and intermediate layer pass through the same skin, hence the following condition (5) holds:
                              d          ∝                                                    D                B                            ·                              C                B                                                                                                                      ⁢                                  d                  ⁢                                                                          ⁢                                      M                    B                                                                              d                ⁢                                                                  ⁢                t                                                    =                                            D              A                        ·                          C                              A                ,                s                                                                                                                    ⁢                              d                ⁢                                                                  ⁢                                  M                  A                                                                    d              ⁢                                                          ⁢              t                                                          (        5        )            in which;                dMA/dt The release rate of the crystalline drug (A) [kg/s]        dMB/dt The release rate of the dissolved drug (B) [kg/s]        d Skin thickness [m]        DA Diffusion coefficient of the crystalline drug (A)        DB Diffusion coefficient of the dissolved drug (B)        CB The concentration of the completely dissolved drug        CA,s Saturation concentration of the crystalline drugFrom equation (5) follows the required concentration of the dissolved drug (B):        
                              C          B                =                                                            d                ⁢                                                                  ⁢                                  M                  B                                                            d                ⁢                                                                  ⁢                t                                                                    d                ⁢                                                                  ⁢                                  M                  A                                                            d                ⁢                                                                  ⁢                t                                              ⁢          x          ⁢                                    D              A                                      D              B                                ⁢          x          ⁢                                          ⁢                      C                          A              ,              s                                                          (        6        )            
Based on mechanistic considerations it can be concluded that the concentration of the dissolved drug (CB) needed to obtain the right release for drug B, may become critically low when the saturation solubility is relatively low and the target release rate relatively high. Equation (6) indicates that concentration of dissolved drug (CB) in the reservoir proportionally depends on the saturation solubility and inversely on the release rate of the crystalline drug (dMA/dt). Hence CB decreases with decreasing saturation solubility CA,s and increasing release rate dMA/dt of the crystalline drug A. The drug-in-polymer diffusion coefficients in equation 6 are an intrinsic property of the polymer-drug pairs and hence these parameters may only coincidentally help to move CB in a higher direction. It can be concluded that CB and hence the amount of dissolved drug B in the delivery system, is tied by the solubility and release rate of drug A. If the amount of drug B dissolved in the reservoir is below a certain level, the release cannot be sustained over the intended duration of use. Certain embodiments of the IVRs described below are designed to overcome this and the other above limitations.